PET117

Inheritance Pattern: Unknown

Disease ID:MONDO:0033654

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0033654

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between PET117 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 13, 2019. 2 articles were reviewed. PET117 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2017 (Renkema et al., PMID: 28386624). The variant reported in this patient is a nonsense variant leading to a premature stop codon. Complex IV deficiency is the disease mechanism for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 1 proband with Leigh syndrome spectrum in 1 publication (PMID 28386624). This gene-disease association is further supported by the function of the gene product and interaction with another protein associated with Leigh syndrome spectrum. In summary, there is limited evidence to support the relationship between PET117 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 13, 2019 (SOP Version 6).

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PET117* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 4, 2024. The *PET11*7 gene encodes a cytochrome *c* oxidase chaperone important for complex IV biogenesis and assembly. The first and only report of *PET117* in relation to autosomal recessive primary mitochondrial disease was in 2017 (PMID: 28386624). *PET117* has been associated with one disease entity to date; mitochondrial complex IV deficiency, nuclear type 19 [OMIM# 619063]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Of note, *PET117* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on May 13, 2019 (SOP v6), with a final classification of Limited. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case from one publication (PMID: 28386624), in a child with LSS. The mechanism of disease is suspected to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 27977873) and functional alteration in non-patient cells (PMID: 37247699). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 4, 2024 (SOP Version 11).